This proposal is for a 5 year renewal (years 16-20) of the Alzheimer's Disease Cooperative Study (ADCS). This consortium of 34 members' sites and 46-56 participating sites is proposing both continued instrument development as well as new clinical drug studies. Instrument development will focus on innovative methods of home based assessments for a broad cohort of normal elderly(over age 75) who may have significant co-morbidities in a simulated primary prevention trial employing mail-in questionnaires, automated telephone technology and computerized data collection to assess cognitive, functional, affective, global, quality of life, and resource use measures in the home environment. The ADCS has assembled its most exciting portfolio of clinical drug trials by seeking new and innovative compounds form the biotechnology sector, individual investigator laboratories as well as from its own members. We are proposing 3 phase 3 efficacy trials of agents designed to slow progression of AD: (1) TTP488, a small novel molecule that binds to and inhibits the receptor for advanced glycation end products (RAGE) which blocks deposition of A?, (2) NAP, a novel eight amino acid peptide derived from the sequence of activity dependent neuroprotective protein(ADNP), the most potent neuroprotectant molecule currently known and (3) docosahexaenoic acid (DHA), an omega-3 fatty acid with anti-amyloid, anti-oxidant, and neuroprotectant effects. Two biomarker trials are proposed to determine if molecules of interest can produce a measurable biological signal for consideration for future efficacy trials: (1) Li, a molecule that blocks phosphorylation of tau protein and (2) resveratrol, a polyphenol derived from plants and red wine that retards the age-dependent deposition and accumulation of CNS A? and amyloid plaques. Finally, we will test the ability of passive immunization using Mg which contains natural anti-amyloid antibodies and has been demonstrated to improve cognition in early clinical trials in AD. Our existing minority recruitment core is being expanded into a general recruitment core focused on maximizing the recruitment of minorities and other subjects into our clinical trials.